Skin cancer is the most common neoplasm in the United States with a lifetime risk nearly equal to that of all other cancers combined. Like other cancers, skin carcinogenesis proceeds via the accumulative acquisition of discrete complimentary genetic events. The purpose of this proposal is to dissect the molecular mechanisms that mediate the roles of oncogenes and tumor suppressors in skin carcinogenesis. Based on previous studies the following is proposed: 1) The epidermis has a strong backup system that compensates for p53 loss, which may include novel p53 family members, such as p73. 2) A murine p53-172H mutant (p53m), which is equivalent to the human p53-175H "hot spot mutation" , may have a gain-of-function that can bypass the compensatory response observed for p53 loss in the epidermis. 3) Activation of the c-ras(Ha) oncogene not only provides the initiation event for skin carcinogenesis, but also contributes greatly to malignant conversion that may be linked to increased genomic instability. 4) Overexpression of the myc oncogene may play a role in skin carcinogenesis and further inhibition of apoptosis by bcl-2 may augment the oncogenic effect of myc. Previously developed transgenic and knockout mouse models, as well as new models will be used to test these hypotheses. The new transgenic models will utilize an inducible, epidermal-specific transgenic/knockout approach which more closely mimics the sporadic focal accumulation of somatic mutations in human tumors. Well-established chemical carcinogenesis protocols and ultraviolet irradiation, which is a critical etiological factor for human skin cancer, will be used as experimental approaches with these mouse models. The development of transgenic models with defined genetic alterations, which have been implicated in human skin cancer, may have a major impact in the development of novel therapeutic approaches in the future.